Project Summary The influence of muscle derived molecules on bone remodeling has been for a long time a topic of intense research in bone biology. Recently we have provided suggestive evidence that interleukin-6 (IL-6) synthesized in, and secreted in the general circulation by myoblasts, is a powerful and positive regulator of the release of the bone-derived hormone osteocalcin. Moreover, classical studies of bone cell biology had proposed twenty five years ago that IL-6 may regulate osteoclast differentiation and some aspects of bone remodeling. In view of both of these classical and more recent observations, the question arises as to know whether muscle-derived IL-6 is a biologically important regulator of bone remodeling at rest or during exercise, in young and/or older mice. A second question is to know whether muscle-derived IL-6 is a significant regulator in vivo of the release of osteocalcin and therefore of the biological activity of this osteoblast-specific secreted molecule. We intend to address these two related questions of bone biology in vivo and through the use of several mouse models of cell-specific deletion for either IL-6 in myoblasts or its receptor in osteoblasts, osteocytes and osteoclasts. To achieve these goals, the Specific Aims of this application are: ? Determine the role of muscle-derived IL-6 in regulating exercise response and bone mass in vivo. ? Delineate the relative influence of IL-6 signaling in cells of the osteoblast or the osteoclast lineage on exercise capacity and bone mass in vivo. ? Determine whether acute or chronic delivery of recombinant osteocalcin is sufficient to increase exercise capacity in wild-type mice as they age.